JP2011219364A - Percutaneous absorption promotor and transdermal formulation containing the percutaneous absorption promotor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a percutaneous absorption promotor for percutaneously absorbing drugs more swiftly for obtaining the proper therapeutic effect of the drugs from the viewpoint of compliance, and a transdermal formulation containing the percutaneous absorption promoter.SOLUTION: The percutaneous absorption promotor is composed of a vinylpyrrolidone polymer and/or copolymer and monoethanolamine.

Description

  The present invention relates to a transdermal absorption enhancer and a transdermal preparation containing the transdermal absorption enhancer.

In transdermal formulations, it has been studied to promote percutaneous absorption of drugs.
For example, a drug such as oxybutynin, which is a urinary agent, is stabilized with polyvinylpyrrolidone (PVP) (Patent Document 1), and a drug such as methotoxalate, which is an antineoplastic agent. Enhance transdermal absorption with organic amines (Patent Document 2), and promote transdermal absorption with alkanolamines for drugs such as anti-inflammatory / analgesic meloxicam (Patent Document 3). .

  While such studies have been made, drugs with PDE4 (Phosphodiesterase 4) inhibitory action such as roflumilast are likely to cause side effects such as nausea and diarrhea if the blood concentration is too high. Therefore, there is a problem that it is difficult to obtain an appropriate therapeutic effect. As for PDE4 inhibitors, there are, for example, a percutaneous absorption treatment system containing roflumilast (Patent Document 4) and an example of transdermal administration to rats. Thus, when a drug having poor absorbability is used as a transdermal preparation, it is forced to administer more than the amount administered orally (Patent Document 5).

International Publication No. 2005/102393 JP 2002-332228 A International Publication No. 2005/123046 Special Table 2002-538207 JP 2005-529930 A

  When a large amount of a drug is administered in a transdermal preparation, there are problems such as that the side effects as described above are caused and an appropriate therapeutic effect of the drug cannot be obtained. Accordingly, an object of the present invention is to provide a transdermal absorption enhancer for percutaneously absorbing a drug and a transdermal preparation containing the transdermal absorption enhancer from the viewpoint of compliance.

  In order to solve the above-mentioned problems, the present inventors surprisingly conducted a research to improve the percutaneous absorption enhancement of drugs, and surprisingly, a polymer of vinylpyrrolidone and / or a co-polymer. As a result of discovering that a percutaneous absorption enhancer comprising a polymer and monoethanolamine exhibits extremely rapid and high percutaneous absorption enhancement and is satisfactory in terms of compliance, and further researched, the present invention It came to complete.

That is, the present invention relates to a percutaneous absorption enhancer comprising a vinylpyrrolidone polymer and / or copolymer and monoethanolamine.
The present invention also relates to the transdermal absorption enhancer, wherein the mass ratio of the vinylpyrrolidone polymer and / or copolymer to monoethanolamine is 1: 0.2 to 1: 5.
Furthermore, the present invention relates to the transdermal absorption enhancer, wherein the vinyl pyrrolidone polymer and / or copolymer is polyvinyl pyrrolidone.
The present invention also relates to the transdermal absorption enhancer described above for promoting the transdermal absorbability of roflumilast and / or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention relates to a transdermal preparation containing a drug and the transdermal absorption enhancer.
The present invention also relates to the above transdermal preparation, wherein the ratio of the mass of the drug to the mass of the transdermal absorption enhancer is in the range of 1: 0.4 to 1:20.
Furthermore, the present invention relates to the transdermal formulation described above, wherein the content of the vinylpyrrolidone polymer and / or copolymer is in the range of 3 to 15% by mass relative to the mass of the transdermal formulation.
The present invention also relates to the above transdermal preparation, wherein the content of monoethanolamine is in the range of 3 to 15% by mass relative to the mass of the transdermal preparation.
Furthermore, the present invention relates to the aforementioned transdermal formulation, wherein the drug is roflumilast and / or a pharmaceutically acceptable salt thereof.

Such a configuration eliminates the problems of the prior art and enables faster percutaneous absorption of the drug, thereby providing a percutaneous absorption enhancer capable of obtaining an appropriate therapeutic effect of the drug, and the percutaneous absorption promotion A transdermal preparation containing the agent can be provided. Thereby, as disclosed in the examples of the present invention, an effective therapeutic effect can be expected even with a smaller drug dose as compared with the conventional transdermal absorption enhancer.
By using a percutaneous absorption enhancer containing a combination of a vinylpyrrolidone polymer and / or copolymer and monoethanolamine, the drug can be passed more rapidly than a transdermal preparation using a conventional percutaneous absorption enhancer. Appropriate therapeutic effects can be obtained by the ability to absorb skin. Furthermore, as shown in the examples, since the percutaneous absorption of the drug is performed more rapidly, a more excellent therapeutic effect such as COPD is expected.

The transdermal absorption enhancer of the present invention comprises a vinylpyrrolidone polymer and / or copolymer and monoethanolamine.
Examples of the vinyl pyrrolidone polymer include, but are not limited to, polyvinyl pyrrolidone or a crosslinked polymer thereof (eg, crospovidone).

Examples of the polyvinylpyrrolidone include Kollidon 12 PF (Kollidon 12 PF: molecular weight 2000-3000), Kollidon 17 PF (Kollidon 17 PF: molecular weight 7000-11000), Kollidon 25 (Kollidon 25: molecular weight 28000-34000), Kollidon 30 (Kollidon 30: molecular weight 44000-54000), Kollidon 90 F (Kollidon 90 F: molecular weight 1000000-1500000), and the like are mentioned. From the viewpoint of further increasing compliance, Kollidon 25, Kollidon 30, and Kollidon 90 F are preferable. .
The average molecular weight of the vinyl pyrrolidone polymer is preferably 2000 or more from the viewpoint of further increasing the compliance, for example.
Examples of the crosslinked polymer include crospovidone, Kollidon CL (BASF), polyplastidone (ISP), and the like.

Examples of the vinyl pyrrolidone copolymer include vinyl pyrrolidone as the main monomer unit, and other examples of the sub monomer unit include vinyl acetate, (meth) acrylic acid ester, acrylic acid, and N-alkyl vinyl pyrrolidone derivatives. . Of these, from the viewpoint of not forming unnecessary salts with monoethanolamine, which is a part of the percutaneous absorption enhancer, vinyl acetate, (meth) acrylic acid ester, and N-alkylvinylpyrrolidone derivatives are preferred. More preferably vinyl acetate.
The transdermal absorption enhancer of the present invention contains monoethanolamine.

The mass ratio of the vinylpyrrolidone polymer and / or copolymer and monoethanolamine in the percutaneous absorption enhancer of the present invention is 1: 0.1 to 1:10, from the viewpoint of further increasing the compliance. The ratio is preferably 1: 0.2 to 1: 5, more preferably 1: 0.5 to 1: 3.
The drug whose percutaneous absorption is promoted by the percutaneous absorption enhancer of the present invention is not particularly limited. For example, a PDE4 inhibitor having a narrow therapeutic area, particularly roflumilast (BY-217), silomilast (trade name) Ariflo), Allofylline, OPC-6535, ONO-6126, IC-485, AWD-12-281, CC-10004, CC-1088, KW-4490, Irimilast, ZK-117137, YM-976, BY-61-9987, CC-7085, CDC-998, MEM-1414, ND-1251, Bay19-8004, D-4396, PD-168787, Atizoram (CP-80633, Cipamphilin (Cipamfy) line) (BRL-61063), Rolipram, NIK-616, SCH-351591 or V-11294A, and pharmaceutically acceptable salts thereof, preferably roflumilast and / or its pharmaceutical Acceptable salt.

その製法も、例えば、特表平８−５１２０４１において記載されている。また、ロフルミラストはＰＤＥ４阻害作用を有し、ＣＯＰＤ（Chronic obstructive pulmonary disease：慢性閉塞性肺疾患）やその他の肺機能改善のための治療薬として期待されている。 Roflumilast is N- (3,5-dichloropyrid-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (N- (3,5-dichloropyridyl-4-yl) -3-cyclopropylmethyoxy-4- difluoromebenzamide (INN)) and has a structure represented by the following formula (I).

The manufacturing method thereof is also described in, for example, JP-T-8-512041. Roflumilast has a PDE4 inhibitory action and is expected as a therapeutic agent for improving COPD (Chronic obstructive pulmonary disease) and other pulmonary functions.

The pharmaceutically acceptable salt of roflumilast is not particularly limited, and may be, for example, an acid or base addition salt, or an N-oxide of a pyridine residue thereof.
Examples of the acid addition salt include hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, Sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or addition salt with 3-hydroxy-2-naphthoic acid, etc. Is mentioned.
Examples of the base addition salt include addition salts with lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine, and guanidine.
Moreover, the preferable dosage of drugs, such as roflumilast, is 0.5-50 mg / day.

The transdermal preparation of the present invention contains a drug and the transdermal absorption enhancer.
The above-mentioned transdermal preparation is not particularly limited as long as it is a preparation for administering a drug through the skin, and its dosage form is aerosol, transdermal absorption preparation, suspension / emulsion, patch, ointment, pap Agent, liniment and the like. Of these, a patch is preferable. Such a patch has, for example, a support layer, a pressure-sensitive adhesive matrix layer containing a drug, and optionally a protective film layer. The protective film layer protects the pressure-sensitive adhesive matrix layer, and is peeled off before use of the preparation, and the preparation is used by attaching the matrix layer to the skin.
The transdermal formulation is preferably substantially free of water. “Substantially no water” means that no water is added or the water content in the preparation is 10% by mass or less. In addition, since inorganic acids, organic acids, carboxyvinyl polymers, and polyacrylic acid may form useless salts with monoethanolamine, it is not always necessary to add them.
In the transdermal preparation, the mass ratio of the drug to the transdermal absorption enhancer comprising vinylpyrrolidone polymer and / or copolymer and monoethanolamine is 1: 0.1 to 1:20. is there. In this range, from the viewpoint of further increasing compliance, it is preferably 1: 0.4 to 1:10, more preferably 1: 1.5 to 1:10, and most preferably 1: 2 to 2. 1: 5.

  The vinylpyrrolidone polymer and / or copolymer in the transdermal preparation of the present invention tends to increase the skin permeability of the drug depending on the amount thereof. It can mix | blend in the range of -30 mass%, From a viewpoint of raising a compliance more, Preferably it is 3-15 mass%. If the blending amount is small, the skin permeability of the drug may not be sufficient. If the blending amount is large, the solubility of the drug increases, so that the rise of skin absorption tends to be slow (that is, the absorption lag time becomes long).

In the transdermal preparation of the present invention, monoethanolamine has a tendency to increase the skin permeability of the drug depending on the amount thereof. From a viewpoint which can mix | blend and raise a compliance more, Preferably, it is 3-15 mass%, More preferably, it is 3-10 mass%. If the blending amount is small, the skin permeability of the drug may be insufficient, and if the blending amount is large, skin irritation may occur.
The drug in the transdermal preparation of the present invention can be blended in the range of 1 to 30% by mass with respect to the total mass of the transdermal preparation. In this range, from the viewpoint of further increasing the compliance, the range is preferably 3 to 15% by mass, and more preferably 3 to 10% by mass.

  The percutaneous absorption enhancer comprising a vinylpyrrolidone polymer and / or copolymer and monoethanolamine can be blended in a range of 2 to 60% by mass with respect to the total mass of the transdermal preparation, and compliance. From the viewpoint of further improving the ratio, it is preferably in the range of 6 to 30% by mass.

EXAMPLES Examples and comparative examples of the present invention will be shown below, and the present invention will be described in more detail. However, the present invention is not limited to these examples.
1. Examination of skin permeation with one type of transdermal absorption enhancer (Comparative Examples 1-12)

[Comparative Example 1]
As a drug, 1 g of roflumilast and 99 g of base are uniformly dissolved in an organic solvent (toluene), and then applied to a 75 μm thick polyethylene terephthalate film as a protective film so that the thickness after drying becomes 100 μm. Then, after removing the solvent by drying, a film made of polyethylene terephthalate having a thickness of 25 μm was laminated as a support layer and appropriately cut to obtain a transdermal preparation.
The base consists of 10 parts by mass of a styrene-isoprene-styrene block copolymer, 18 parts by mass of an alicyclic saturated hydrocarbon resin, and 5 parts by mass of liquid paraffin.

[Comparative Example 2]
A transdermal preparation was obtained in the same manner as in Comparative Example 1 except that 94 g of the base and 5 g of monoethanolamine were used as the transdermal absorption enhancer.
[Comparative Examples 3 to 12]
Each transdermal preparation was obtained in the same manner as in Comparative Example 2 except that 5 g of each of the percutaneous absorption enhancers shown in Table 1 was added as an additive.

[Measurement of skin permeation]
About the produced said preparation, the following skin permeation test was done and the skin permeation amount was calculated | required.
The skin of the skin attached to a flow-through skin permeation test cell (3 cm ² ) with the skin of the body of a hairless mouse peeled off, the dermis side facing the receptor layer, and hot water of 32 ° C. was circulated around the outer periphery. The preparations prepared as described above were affixed to the layer side.
As the receptor solution, a phosphate buffer solution (pH 7.4) containing 40% of PEG 400 was replaced at a predetermined rate, and the solution was collected every 24 hours for up to 24 hours for drug quantification.
The concentration of roflumilast for each time is quantified by high performance liquid chromatography and the cumulative drug permeation amount is shown in the rightmost column of each table below.

The skin permeation amount of roflumilast was compared with roflumilast and various compounds as percutaneous absorption enhancers in the base. As shown in Table 1, monoethanolamine (Comparative Example 2) was skin permeation of roflumilast. Found to increase the most.
Further, as shown in Comparative Example 12, polyvinyl pyrrolidone alone showed only the percutaneous absorbability comparable to other percutaneous absorption enhancers.

2. Examination of skin permeation with monoethanolamine and one type of transdermal absorption enhancer (Example 1 and Comparative Examples 13-17)
[Example 1]
A transdermal preparation was prepared in the same manner as in Comparative Example 1, except that 89 g of the base, 5 g of monoethanolamine and 5 g of polyvinylpyrrolidone (Kollidon 30, hereinafter the same) were used as the percutaneous absorption enhancer.
[Comparative Examples 13-17]
Each transdermal preparation was prepared in the same manner as in Example 1 except that 5% by mass of each transdermal absorption enhancer shown in Table 2 was added instead of monoethanolamine and polyvinylpyrrolidone.

  When the skin permeation amount of roflumilast was blended with roflumilast and monoethanolamine and other percutaneous absorption enhancers in the base, the combination of monoethanolamine and polyvinylpyrrolidone as shown in Table 2 (Examples) 1) was found to increase the skin permeability of roflumilast most.

3. Examination of skin permeation with polyvinylpyrrolidone and one type of transdermal absorption enhancer (Example 1 and Comparative Examples 18-25)
[Comparative Examples 18-25]
Each transdermal preparation was prepared in the same manner as in Example 1 except that 5 g of each transdermal absorption enhancer was added.

基剤中にロフルミラストと、ポリビニルピロリドンおよび他の経皮吸収促進剤を配合してロフルミラストの皮膚透過量を比較したところ、表２のように、モノエタノールアミンとポリビニルピロリドンとの組合せ（実施例１）が、ロフルミラストの皮膚透過性を最も高めることを見出した。

When the skin permeation amount of roflumilast was blended with roflumilast and polyvinylpyrrolidone and other percutaneous absorption enhancers in the base, the combination of monoethanolamine and polyvinylpyrrolidone (Example 1) was compared as shown in Table 2. ) Was found to increase the skin permeability of roflumilast most.

4). Examination of skin permeation amount by blending ratio of monoethanolamine and polyvinylpyrrolidone (Examples 1-8 and Comparative Examples 1, 2 and 12)
[Examples 1-8, Comparative Examples 1, 2 and 12]
Each transdermal preparation was prepared in the same manner as in Example 1 with the composition shown in Table 4.

A transdermal formulation containing 5% by mass or more of monoethanolamine showed a larger amount of skin permeation. Moreover, the transdermal formulation containing 5% by mass or more of polyvinylpyrrolidone showed a larger skin permeation amount.
The ratio of roflumilast mass to the total mass of MEA and PVP showed excellent skin permeation in any of 1: 1.5 to 1:10 compared to the comparative example, but it was 1: 2 to 1: 5. In the range, a particularly large amount of skin permeation was shown.

Claims (9)

  A transdermal absorption enhancer comprising a vinylpyrrolidone polymer and / or copolymer and monoethanolamine.   The transdermal absorption enhancer according to claim 1, wherein the mass ratio of the vinylpyrrolidone polymer and / or copolymer and monoethanolamine is 1: 0.2 to 1: 5.   The transdermal absorption enhancer according to claim 1 or 2, wherein the vinyl pyrrolidone polymer and / or copolymer is polyvinyl pyrrolidone.   The transdermal absorption enhancer according to any one of claims 1 to 3, which is used for promoting transdermal absorbability of roflumilast and / or a pharmaceutically acceptable salt thereof.   A transdermal preparation containing a drug and the transdermal absorption enhancer according to any one of claims 1 to 4.   The transdermal preparation according to claim 5, wherein the ratio of the mass of the drug to the mass of the transdermal absorption enhancer is in the range of 1: 0.4 to 1:20.   The transdermal preparation according to claim 5 or 6, wherein the content of the vinylpyrrolidone polymer and / or copolymer is in the range of 3 to 15 mass% with respect to the mass of the transdermal preparation.   The transdermal preparation according to any one of claims 5 to 7, wherein the content of monoethanolamine is in the range of 3 to 15 mass% with respect to the mass of the transdermal preparation.   The transdermal preparation according to any one of claims 5 to 8, wherein the drug is roflumilast and / or a pharmaceutically acceptable salt thereof.